Polymorphisms of the HSD11B1 gene as phenotype modifiers in women with hypercortisolism
K Feldman1, A Szappanos1, I Liko2, B Acs1, M Toth1, A Patocs3,4 & K Racz1
Objective: Several studies including ours have reported significant associations between polymorphisms (SNPs) of the HSD11B1 gene and bone metabolism. The aim of the present study was to explore systematically the potential associations between SNPs of the HSD11B1 gene and bone mineral density (BMD) in women with endogenous Cushings syndrome (CS) and healthy postmenopausal women.
Patients and methods: A complex bioinformatical including haplotype analysis was performed for identification of SNPs located in the HSD11B1 gene and its 15 kb promoter sequence. Of the 65 polymorphisms found in this region 7 (rs11576775, rs17389016, rs4844880, rs84910, the previously explored insA, rs12086634, and rs11807619) were selected for further analysis. Sixty-two women with endogenous hypercortisolism (35 patients with ACTH-producing pituitary adenomas: Cushings disease, CD; 27 patients with cortisol-producing adrenal tumors, ACS) and 94 healthy control women were examined. Genotyping was performed by real-time PCR and direct DNA sequencing. BMD was measured by dual-energy X-ray absorptiometry.
Results: No differences in polymorphic allele frequencies between patients and controls were detected. The insA, rs12086634 and rs11807619 were in linkage disequilibrium. Haplotype containing insA, polymorphism rs12086634 and wild-type rs11807619 was associated with better BMD in healthy women and in patients with ACS but not in patients with CD. Serum OC was higher in carriers for this haplotype. The rs4844880 located in the promoter region was associated with higher BMD, and in patients with CD with higher BMI, OC and cortisol measured morning, midnight and after low dose dexamethasone suppression compared to non-carriers.
Conclusions: Our results suggest that SNPs of the HSD11B1 gene may modulate the glucocorticoid effects on bone metabolism and represent genetic modyfiers of BMD. In patients with endogenous hypercortisolisms these SNPs may contribute to the severity of the disease.